Permethrin is chemically known as 3-phenoxybenzyl (1RS,3RS;1RS,3SR)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate.
Permethrin is a photostable synthetic pyrethroid and it is a mixture of four stereoisomers of the configuration ([1R,3S trans], [1R,3R cis], [1S,3R trans], and [1S, 3S cis]). The optical ratio of 1R:1S is 1:1 in a racemic mixture.
1R cis isomer 1S cis isomer 1R trans isomer 1S trans isomer
It is marketed as Elimite in the US as a topical cream for the treatment of scabies caused by Sarcoptes scabiei, which is one of the primary indication treated by Permethrin. The cis: trans isomeric ratio in this product is 1:3 i.e. 25:75.
U.S. Pat. No. 4,024,163 describes the esterification of dichloro analogue of chrysanthemic acid, i.e. [1R-trans]-2,2-dimethyl-3-(2,2-dichlorovinyl) cyclopropane carboxylic acid with 3-phenoxybenzyl alcohol. The desired isomeric ratio of the final product Permethrin (1) is obtained by separating the isomers of the precursor acid chloride and subsequently condensing with (3-phenoxyphenyl) methanol.
U.S. Pat. No. 4,113,968 describes the process for the preparation of Permethrin (1), which involves base hydrolysis of ethyl 2,2-dimethyl-3-(2′,2′-dichlorovinyl)-cyclopropane-carboxylate in presence of potassium hydroxide and methanol to obtain acid, which is further treated with thionyl chloride to obtain 2,2-dimethyl-3-(2′,2′-dichlorovinyl)-cyclopropane-carboxylic acid chloride. The obtained acid chloride compound (either cis or trans) was coupled with 3-phenoxybenzyl alcohol in the presence of pyridine in benzene as a solvent, to obtain 3-phenoxybenzyl-2′,2′-dimethyl-3′-(2″,2″-dichlorovinyl)-cyclopropane-carboxylate.
Indian patent IN253251 describes the coupling of 2,2-dimethyl-3-(2′,2′-dichlorovinyl)-cyclopropane-carboxylic acid chloride with 3-phenoxybenzyl alcohol without using any solvent at temperature 60-80° C. and continuously expelling hydrochloric acid during the reaction mass into a hydrochloride gas scrubber and washing the crude product to obtain Permethrin (1).
Permethrin produced in the prior art processes suffers from drawbacks like low yield, and lesser purity of the final compound. Further, Permethrin synthesized in the prior art is not purified and carries inherent reaction impurities. To overcome the problems associated with prior art, there is a need to develop an efficient method for commercial scale production of pharmaceutical grade Permethrin, with desired isomeric purity and which is free of reaction impurities.